APTO-253

To investigate the therapeutic potential of three G4 ligands-pidnarulex, APTO-253, and BRACO-19-a high-throughput drug combination screen was conducted in thirty-one multi-cell type tumor spheroids derived from patient tumors and established cancer cell lines. Brightfield imaging corroborated enhanced spheroid growth suppression from synergistic combinations. These findings underscore the context-dependent activity of G4 ligands and support the use of integrated functional and imaging-based approaches to characterize potential therapeutic combinations in physiologically relevant 3D cancer models.

Furthermore, we found that APTO-253, a small-molecule inducer of KLF4, effectively suppressed cell growth in TALL-1 cells by promoting T-cell differentiation followed by apoptotic cell death. These findings suggest a promising strategy for developing novel differentiation therapies for T-ALL with NOTCH3 mutations.

Additionally, our data suggest a link between the induced expression of MICA and the regulation of both, KLF4 and c-MYC, which might represent a mechanism underlying the induction of NKG2D-L expression upon treatment with APTO253. These results may contribute to the potential use of APTO253 as a treatment to improve tumor cell-mediated NK cell cytotoxicity in various cancers.

In addition, we found that APTO-253, a small molecule inducer of KLF4, exerts an anti-leukemic effect by targeting SE-driven TAL1 expression in T-ALL cells. Taken together, our results suggest that the induction of KLF4 is a promising strategy to control TAL1 expression and could be a novel treatment for T-ALL patients with a poor prognosis.

Finally, we investigated whether pharmacological induction of KLF4 using APTO-253, a small-molecule inducer of KLF4, could control leukemia...Moreover, pharmacological induction of KLF4 demonstrated anti-leukemic activity in T-ALL cells. These findings propose a promising strategy for patients with T-ALL and 5' TAL1 SE.

In addition, APTO-253 has the potential to become an AML-targeted drug. The cuproptosis-related genes MTF1 and LIPT1 can be used as prognostic biomarkers in AML. A total of six lncRNAs, including MALAT1, are involved in the expression and regulation of MTF1 in AML through six miRNAs such as hsa-miR-32-5p.

These data unravel a novel link between APTO253 and the innate anti-tumor immune response providing a rationale for targeting AML cells via APTO253-dependent KFL4/MICA induction to allow elimination by endogenous or transplanted NK and T cells in vivo. Video Abstract.

APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting.

PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253)3 in serum and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m2 dose level is ongoing and updated clinical data will be presented at the meeting.

Furthermore, treatment of TNBC cells with a KLF4-inducing small compound, APTO-253, resulted in the induction of NOXA expression and NOXA-mediated apoptosis. Therefore, our results help to clarify the molecular mechanism of DNA damage-induced apoptosis and provide support for a possible treatment method for p53-mutated cancers.

Based on its broad efficacy and limited toxicity, OmoMYC is currently being developed for evaluation in clinical trials. Although no compound directly targeting MYC has yet progressed to clinical testing, APTO-253, which partly acts by decreasing expression of MYC, is currently undergoing a phase I clinical trial in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

APTO-253 has been well-tolerated in patients treated with 20, 40, 66, and 100 mg/m2 over multiple cycles. PK analysis revealed APTO-253 monomer rapidly transformed to and co-existed with the Fe(253)3 complex in peripheral blood and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m2 dose level is underway and updated clinical data will be presented at the meeting.